Cerebrospinal Fluid Cytokines in Diagnosis of Acute Bacterial Meningitis

Aggrawal P, Agrawal A and Prasad R*

Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

*Corresponding author: Prasad R, Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Received: January 15, 2017; Accepted: February 13, 2017; Published: February 15, 2017

Abstract

Acute bacterial meningitis in children is associated with high mortality and morbidity in developing countries including India due to poor immunization coverage, delayed diagnosis and lack of appropriate treatment. Although Cerebrospinal Fluid (CSF) microscopic and routine examination has been used as a tool to diagnose bacterial meningitis, it has poor sensitivity and specificity. Detection of cytokines such as TNF a, IL-6 and IL-8 in the CSF has been suggested for early diagnosis and differentiation of various etiological subgroups of meningitis. This review aims to summarize the diagnostic performance of these cytokines for the same in various studies in existing literature.

Keywords: Meningitis; Tumour Necrosis Factor (TNF-a); Interleukin- 6(IL-6); IL-8

Introduction

Acute Bacterial Meningitis is a life threatening condition associated with high mortality and morbidity. Although bacterial meningitis account for only minority (approximately 5%) of the total cases, it is the most severe form and associated with mortality ranging from 2% in infants and children to as high as 30% in neonates and adults [1,2]. The case fatality rates are even worse in developing countries with various reported mortality rates of 37 to 60% despite use of appropriate therapeutic and diagnostic advancements in contrast to the developed nations. The difference in mortality can be attributed to poor immunization coverage, delayed diagnosis and lack of appropriate treatment in developing countries. Patients who survive, 1/3^rd are left with various neurological sequelae such as deafness, blindness, motor deficit or cognitive impairment [3].

The diagnosis of bacterial meningitis although primarily relies upon CSF examination [4], has poor sensitivity and specificity in differentiating the etiological subgroups [5], Clinical assessment, cytology, CSF culture, Gram’s staining, biochemical test and newer tests such as CSF CRP, serum procalcitonin, CSF cytokines and CSF PCR have been used to diagnose and differentiate bacterial from nonbacterial causes of meningitis. As none of these tests is unequivocally optimal, empirical use of antibiotics have resulted in unnecessary hospitalization and increased cost [4-6].

Cytokines in Diagnosis

Cytokines (mainly TNF a, IL6 and IL8), chemokines, proteolytic enzymes, and oxidants play an important role in inflammatory cascade and brain dysfunction associated with bacterial meningitis [7]. Tumor necrosis factor-alpha (TNF-a) is a potent activator of neutrophils and mediates adherence, chemo taxis, degranulation, and the respiratory burst. Interleukin-6 (IL-6) stimulates the growth of B lymphocytes that have differentiated into antibody producing cells. Interleukin-8 (IL-8) acts as a chemo attractant for neutrophils to the site of inflammation. IL-6-deficiency has been shown to result in higher CNS bacterial colonization and lower survival in murine model [8]. A higher concentration of TNF-a, IL-6 and IL-8 in patients with bacterial meningitis has been reported in various studies and has been successfully used in early diagnosis as well as differentiating bacterial and viral meningitis [9]. Various studies have found them to be the most sensitive and specific inflammatory markers of bacterial meningitis [10,11].

Literature Review on Cytokines

Cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1β, IL-8, and IL-6 are expressed in the CNS after local bacteria inoculation and are detectable up to 96 hours [12,13]. The elevated levels of these cytokines in the CSF, implies their role in the pathogenesis of bacterial meningitis and can be used in diagnosis and monitoring the treatment response. No association of these cytokines has been reported with the subsequent development of neurological sequelae. Studies have indicated that elevated levels of these cytokines may not be evident in the serum, as their expression may be a local and compartmentalized phenomenon [14].

A significant increase in CSF cytokines levels in the cases of meningitis has been demonstrated in many studies, adding to the diagnostic potential of their analysis.12-14 Most significant of these cytokines are TNF-a, IL-6 and IL-8 [15,16]. Although there are few studies that failed to reveal a statistically significant difference in IL-6 levels between meningitis and non- meningitis groups, but the substantial evidence suggesting significant association cannot be neglected [17,18]. It should be noted that there have been studies reporting elevation of CSF IL-6 in patients of traumatic brain injuries as well, however can easily excluded by a careful clinical history [19]. The elevated cytokines levels can be used to differentiate between bacterial, viral and tubercular etiology as studies have shown higher levels of cytokine (TNF- a, IL-6 and IL-8) in acute bacterial meningitis compared to others [20,21]. These studies have revealed sensitivity and specificity approaching 100%, making this test highly valuable [22-24].

Few studies that assessed each cytokine level individually, failed to demonstrate a significant differences between septic and aseptic meningitis [17,19,25] As there is a positive significant association between different cytokines14, a battery of tests consisting of TNF- a, IL-6 and IL-8 can be done to alleviate any confusion or false negative results. There is no evidence of any association between cytokines and routinely measured CSF parameters [14,21]. These tests can also be performed to differentiate between lymphocytic predominant meningitis and partially treated septic meningitis with high sensitivity and specificity [22], however no significant association has been found between meningitis causing bacterial species and CSF cytokine values (Table 1).

Download PDF

Citation: Aggrawal P, Agrawal A and Prasad R. Cerebrospinal Fluid Cytokines in Diagnosis of Acute Bacterial Meningitis. Austin Pediatr. 2017; 4(1): 1049. ISSN:2381-8999

Instruction for Authors

Submit Your Article

Study	Year			Sample size (Bacterial Meningitis)		Sample size (Non Bacterial Meningitis)		Assay Method		Cut off value		Sensitivity (%)			Specificity (%)
TNF a
Nadal D et al [28]	1989			18		31		ELISA		500 pg/ml		NA			NA
Glimâker M et al [29]				1993				51				78
Tang RB et al [11]		2001			23			26			74			81
Mukai AO et al [15]			2006				6		13				ELISA
Prasad R et al [20]	2014			57		30		ELISA		500 pg/ml		100			100
IL-6
Dulkerian SJ et al [30]	1995			20		42		ELISA		NA		100			79
Hashim IA et al [31]	1995			123		123		Radioimmunoassay		3.4 ng/ml		93			95
Kleine TO et al [32]	2003			40		46		SPSCI		2500 ng/ml		92			93
Hsieh CC et al [24]	2009			12		41		ELISA		10 pg/ml		92			51
Chen Z et al [33]	2012			22		61		Radioimmunoassay		51.6 ng/ml		64			95
Vázquez JA et al [26]	2012			13		27		ELISA		90 pg/ml		92			100
Takahashi W et al [22]	2014			13		57		CLEIA		644 pg/ml		92			89
Prasad R et al [20]	2014			57		30		ELISA		100 pg/ml		96			100
IL-8
Ostergaard C et al [34]	1996			31		13		ELISA		3μg/L		81			92
Kleine TO et al [32]	2003			40		46		SPSCI		4000 ng/L		48			91
Pinto Junior VL et al [35]	2011			9		18		ELISA		1.685 ng/dl		100			94
Chen Z [33]	2012			22		61		Radioimmunoassay		1.14 pg/ml		91			67
Prasad R et al [20]	2014			57		30		ELISA		75 pg/ml		100			100
Abdelmoez AT et al [23]	2014			40		40		ELISA		3.6 ng/ml		83			85

Cerebrospinal Fluid Cytokines in Diagnosis of Acute Bacterial Meningitis

Abstract

Introduction

Cytokines in Diagnosis

Literature Review on Cytokines

Prognostic Significance

Conclusion

References